6O61

Tubulin-RB3_SLD-TTL in complex with compound ABI-231

6O61 の概要

• エントリーDOI: 10.2210/pdb6o61/pdb
• 関連するPDBエントリー: 6O5M 6O5N
• 分子名称: Tubulin alpha-1B chain, [2-(1H-indol-3-yl)-1H-imidazol-5-yl](3,4,5-trimethoxyphenyl)methanone, PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER, ... (12 entities in total)
• 機能のキーワード: microtubule inhibitor, colchicine, cancer, cell cycle
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 265041.28

構造登録者

Kumar, G.,Wang, Y.,Li, W.,White, S.W. (登録日: 2019-03-05, 公開日: 2019-07-10, 最終更新日: 2024-03-13)

主引用文献

Wang, Q.,Arnst, K.E.,Wang, Y.,Kumar, G.,Ma, D.,White, S.W.,Miller, D.D.,Li, W.,Li, W.
Structure-Guided Design, Synthesis, and Biological Evaluation of (2-(1H-Indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl) Methanone (ABI-231) Analogues Targeting the Colchicine Binding Site in Tubulin.
J.Med.Chem., 62:6734-6750, 2019

PubMed Abstract: ABI-231 is a potent, orally bioavailable tubulin inhibitor that interacts with the colchicine binding site and is currently undergoing clinical trials for prostate cancer. Guided by the crystal structure of ABI-231 in complex with tubulin, we performed structure-activity relationship studies around the 3-indole moiety that led to the discovery of several potent ABI-231 analogues, most notably and . The crystal structures of and in complex with tubulin confirmed their improved molecular interactions to the colchicine site. In vitro, biological studies showed that new ABI-231 analogues disrupt tubulin polymerization, promote microtubule fragmentation, and inhibit cancer cell migration. In vivo, analogue not only significantly inhibits primary tumor growth and decreases tumor metastasis in melanoma xenograft models but also shows a significant ability to overcome paclitaxel resistance in a taxane-resistant PC-3/TxR model. In addition, pharmacological screening suggested that has a low risk of potential off-target function.

PubMed: 31251599
DOI: 10.1021/acs.jmedchem.9b00706

実験手法

X-RAY DIFFRACTION (2.599 Å)